Retinol binding protein 4 (hereinafter sometimes to be abbreviated as “RBP4”) is known to be a sole blood retinol transport protein mainly produced in the liver. In recent years, moreover, RBP4 is suggested to be an insulin resistance-inducing factor from the following literatures and the like.
(1) Since RBP4 expression increases in the adipocytes of GLUT4 knockout mouse showing insulin resistance, RBP4 is suggested to be a potential adipocytokine inducing insulin resistance (see Nature 436, 356-362 (2005)).
(2) It has been reported that RBP4 overexpression mouse shows hyperglycemia and hyperinsulinemia, and RBP4 knockout mouse shows promotion of glucose tolerance and insulin sensitivity as phenotype (see Nature 436, 356-362 (2005)).
(3) It has been reported that mouse bred on a high-fat diet shows high blood. RBP4 value, which is correlated with induction of insulin resistance (see Nature 436, 356-362 (2005)).
(4) It has been reported that disease model mouse showing diabetes•obesity pathology such as ob/ob mouse, 11β-HSD1 overexpression (adipose tissue specific) mouse, MC4R knockout mouse, GLUT4 knockout (adipose tissue•skeletal muscle specific) mouse and the like also shows high blood RBP4 value (see Nature 436, 356-362 (2005)).(5) It has been reported that blood RBP4 concentration and insulin sensitivity•sugar disposal rate are inversely correlated in human. It has also been reported that the glucose infusion rate decreases as the blood RBP4 concentration increases in euglycemic hyperinsulinemic glucose clamp test (see Cell Metab., 6, 79-87 (2007)).(6) While exercise is known to improve insulin sensitivity, an extremely high correlation between such an improving effect and lowering of blood RBP4 concentration has been reported recently (see N. Engl. J. Med., 354, 2552-2563 (2006)).(7) WO2005-059564 describes that a compound that controls RBP4% activity is useful for the treatment of insulin resistance.
All these suggest that a compound capable of lowering blood RBP4 concentration can be a therapeutic drug for diabetes.
RBP4 is stably present in blood in the form of a complex resulting from the binding of retinol and TTR (transthyretin). When RBP4 is dissociated from TTR and becomes free, it is decomposed in and excreted from the kidney comparatively rapidly. It is unknown whether the binding of RBP4 and retinol is indeed essential for the formation of a complex with TTR. However, fenretinide, a retinol derivative, inhibits the binding of RBP4 and retinol, and consequently inhibits formation of a complex with TTR. It is known that administration of fenretinide to animal induces lowering of blood RBP4 (see Biochim. Biophys. Acta, 1294, 48-54 (1996)).
From the foregoing findings, a compound that inhibits formation of a complex of RBP4 and TTR by inhibiting the binding of RBP4 and retinol is expected to lower blood RBP4 concentration and consequently induce correction of hyperglycemia and improvement of insulin resistance.
In recent years, moreover, a report has documented that blood RBP4 value and blood TG (triglyceride) or LDL cholesterol value positively correlate in human, and blood RBP4 value negatively correlates with HDL cholesterol value (see J. Atheroscler. Thromb., 13, 209-215 (2006), N. Engl. J. Med., 355, 1392-1395 (2006), Diabetes, 56 (Supplement 1), A378 (1477-P) (2007)), thus suggesting relationship with lipid metabolism.
In view of the above, a medicament having an action to lower blood RBP4 value (concentration) (also referred to as “RBP4 lowering action” in the present specification) (also referred to as “RBP4 lowering agent” in the present specification) is expected to be widely applicable to lifestyle-related diseases.
WO 2006/023778 describes a compound represented by the formula:
wherein E is phenyl, heteroaryl; X, Y and Z show H, OH, alkyl, alkoxy and the like; U and W show CO, SO, SO2, S, NH and the like; n is 1 or 2; Q is H, alkyl and the like; and R1 and R2 show H, alkyl, alkenyl, heterocycle and the like.
JP-A-53-31669 describes a compound represented by the formula:
wherein X is lower alkyl, lower alkoxy, halogen; n is 1 or 2 (when n is 2, X may be the same or different), which is useful as a therapeutic agent for ulcer.
WO 02/055501 describes a compound represented by the formula:
wherein A1 and A2 are C, N; A is a 5- or 6-membered aromatic heterocyclic group;X is
Y is
and the like; Z is O, S; Ra and Rb show H, halogen and the like; R1 is H, halogen and the like; R2 is an optionally substituted 6- to 10-membered aryl group; R3 is an optionally substituted aryl group; R4 is a bond, a C2-4 alkenyl group and the like; R5a is H, lower alkyl and the like; R7 is H, lower alkyl, an optionally substituted heterocycle-C1-6 alkyl group, which is useful for the treatment of cancer.    patent document 1: WO2005/059564    patent document 2: WO2006/023778    patent document 3: JP-A-53-31669    patent document 4: WO02/055501    non-patent document 1: Nature 436, 356-362 (2005)    non-patent document 2: Cell Metab., 6, 79-87 (2007)    non-patent document 3: N. Engl. J. Med., 354, 2552-2563 (2006)    non-patent document 4: Biochim. Biophys. Acta, 1294, 48-54 (1996)    non-patent document 5: J. Atheroscler. Thromb., 13, 209-215 (2006)    non-patent document 6: N. Engl. J. Med., 355, 1392-1395 (2006)    non-patent document 7: Diabetes, 56(Supplement 1), A378 (1477-P) (2007)